We previously conducted a comprehensive analysis of transcription of a candidate histone methyltransferase, Setdb2, in human and mouse tissues, revealing tissue-specific expression of alternatively spliced and chimeric transcripts. We found in-frame fusion transcripts linking Setdb2 to an adjacent independent gene, Phf11, which encodes a zinc finger-containing plant homeodomain motif. We previously found several protein-binding partners for the putative histone methyltransferases using yeast two hybrid screens; most of these binding partners now have been validated by co-immunoprecipitation experiments. Further functional characterization of interactions between Setdb2 and the identified binding partners, which include an unannotated protein and other biologically interesting proteins, has been conducted. We have generated a viable, hypomorphic knockout mouse model lacking 70-80% of Setdb2 transcripts and probably most or all encoded proteins. Phenotypic characterization of these knockouts on various mouse strain backgrounds has begun. Occasional homozygous hypomorphic mice with a B cell developmental defect have been identified, suggesting they may suffer from a pre-CLL disease process. The knockout mice could comprise a new model for chronic lymphocytic leukemia, for asthma, and/or for other cancers or human diseases. Specific antibodies against mouse and human Setdb2 have been developed. We have expressed recombinant Setdb2 in baculovirus to facilitate characterization of its biochemical activities. On a preliminary basis, we have shown that Setdb2 is an active histone methyltransferase and may also methylate other cellular proteins.